Bridging the genotype-phenotype gap for a Mediterranean pine by semi-automatic crown identification and multispectral imagery.
Progress in high-throughput phenotyping and genomics provides the potential to understand the genetic basis of plant functional differentiation. We developed a semi-automatic methodology based on unmanned aerial vehicle (UAV) imagery for deriving tree-level phenotypes followed by genome-wide association study (GWAS). An RGB-based point cloud was used for tree crown identification in a common garden of Pinus halepensis in Spain. Crowns were combined with multispectral and thermal orthomosaics to retrieve growth traits, vegetation indices and canopy temperature. Thereafter, GWAS was performed to analyse the association between phenotypes and genomic variation at 235 single nucleotide polymorphisms (SNPs). Growth traits were associated with 12 SNPs involved in cellulose and carbohydrate metabolism. Indices related to transpiration and leaf water content were associated with six SNPs involved in stomata dynamics. Indices related to leaf pigments and leaf area were associated with 11 SNPs involved in signalling and peroxisome metabolism. About 16-20% of trait variance was explained by combinations of several SNPs, indicating polygenic control of morpho-physiological traits. Despite a limited availability of markers and individuals, this study is provides a successful proof-of-concept for the combination of high-throughput UAV-based phenotyping with cost-effective genotyping to disentangle the genetic architecture of phenotypic variation in a widespread conifer.


An apical-membrane chloride channel in human tracheal epithelium.
The mechanism of chloride transport by airway epithelia has been of substantial interest because airway and sweat gland-duct epithelia are chloride-impermeable in cystic fibrosis. The decreased chloride permeability prevents normal secretion by the airway epithelium, thereby interfering with mucociliary clearance and contributing to the morbidity and mortality of the disease. Because chloride secretion depends on and is regulated by chloride conductance in the apical cell membrane, the patch-clamp technique was used to directly examine single-channel currents in primary cultures of human tracheal epithelium. The cells contained an anion-selective channel that was not strongly voltage-gated or regulated by calcium in cell-free patches. The channel was also blocked by analogs of carboxylic acid that decrease apical chloride conductance in intact epithelia. When attached to the cell, the channel was activated by isoproterenol, although the channel was also observed to open spontaneously. However, in some cases, the channel was only observed after the patch was excised from the cell. These results suggest that this channel is responsible for the apical chloride conductance in airway epithelia.


Controlling the heart via the brain: a potential new therapy for orthostatic hypotension.
Electrical stimulation of the midbrain is known to influence blood pressure in animals. In humans, it is used for the treatment of chronic neuropathic pain. Our aim was to assess whether orthostatic hypotension can be successfully treated with deep brain stimulation of the periventricular/periaqueductal gray areas in humans. We recruited 11 patients who had chronic neuropathic pain and who had undergone implantation of a deep brain stimulator in the periventricular/periaqueductal gray areas. Patients were divided into three groups depending on whether they had orthostatic hypotension (one patient), mild orthostatic intolerance (five patients), or no orthostatic intolerance (five patients). Postoperatively, we continuously recorded blood pressure and heart rate with stimulation off and on and in both sitting and standing positions. From these values, we derived the blood pressure changing rate. Using autoregressive modeling techniques, we calculated changes in low- and high-frequency power spectra of heart rate and baroreflex sensitivity. Electrical stimulation reduced the decrease in systolic blood pressure on standing from 28.2 to 11.1% in one patient with orthostatic hypotension (P < 0.001). In the mild orthostatic intolerance group, an initial drop in systolic blood pressure of 15.4% was completely reversed (P < 0.001). There were no side effects in the remaining group. These changes were accompanied by increases in the blood pressure changing rate, the baroreflex sensitivity, and the baseline (sitting) low-frequency power of the RR interval, but not the high-frequency power. Electrical stimulation of the human periventricular/periaqueductal gray areas can reverse orthostatic hypotension. The cause seems to be an increase in sympathetic outflow and in baroreflex sensitivity. This has important implications for future therapies.


First Report of Impatiens necrotic spot virus in Mexico in Tomatillo and Pepper Plants.
Mexico contributes 20% of the total worldwide pepper exports (1). Impatiens necrotic spot virus (INSV) (genus Tospovirus; family Bunyaviridae) has emerged and has possibly caused diseases in various crops and ornamentals in Mexico. INSV was treated as a quarantine virus in Mexico (2) but not anymore. During the growing seasons of 2009 to 2011, surveys were conducted in the counties of Guanajuato and Querétaro in the states of the same names. Sampling included tomatillo (Physalis ixocarpa) and pepper (Capsicum spp.) plantations where plants with possible viral symptoms were observed. The symptoms observed were dark necrotic spots on some leaves and on the stems. These were similar to those observed elsewhere (3). Leaf spots further developed into localized necrotic areas. Using ELISA (Agdia, Elkhart, IN) with polyclonal antibodies, all collected samples showing symptoms tested positive for INSV and negative for Alfalfa mosaic virus (AMV), Cucumber mosaic virus (CMV), Potato X virus (PVX), Potato Y virus (PVY), Tobacco mosaic virus (TMV), Tomato spotted wilt virus (TSWV), Tobacco ringspot virus (TRSV), and Tomato ringspot virus (ToRSV). In order to identify the causal agent of these symptoms, INSV-specific sequences available for the S genomic fragments were obtained from NCBI GenBank. They were aligned and used to design primers to amplify a 250-bp fragment from total extracted RNA from healthy and symptomatic plants using reverse transcription (RT)-PCR. Primers used were INSVF (5'CCCAACTGCCTCTTTAGTGC3') and INSVR (5'GGACAATGGATCTGCTCTGA3'). Three extracted plasmids, each containing an amplified and cloned fragment for the pepper and tomatillo isolates, were sequenced (GenBank Accession Nos. KC503051 and KC503052, respectively). Both nucleotide sequences showed 95% identity with the Chinese, Italian, and Japanese INSV sequences (FN400773, DQ425096, and AB207803, respectively) and 94% identity to other INSV isolates (4). The putative Mexican INSV pepper isolate, derived from a necrotic spot, was mechanically inoculated to other experimental host plants after grinding 1 g of symptomatic leaf tissue in 3 ml of a buffer with quaternary ammonium salts at 0.5%, pH 7.8. Ten plants, at the second true-leaf stage, of each Capsicum annuum cv. cannon and Citrullus lanatus were inoculated after carborundum abrasion of the second true leaf. At 15 days post inoculation, systemic chlorotic necrotic spots, stunting, and apical malformation were observed in capsicum plants while wilting was shown in watermelon plants. RT-PCR analyses and nucleotide sequence of the amplified product confirmed the presence and identity of both virus isolates. To our knowledge, this is the first report of INSV in Mexico found naturally in tomatillo and pepper and experimentally in watermelon plants. Derived from this report, INSV distribution in Mexico should be studied due to its potential impact on these two economically important crops. References: (1) Food and Agriculture Organization of the United Nations. FAOSTAT, retrieved online at http://faostat.fao.org , 2013. (2) DGSV-CNRF. Impatiens necrotic spot virus (INSV). SAGARPA-SENASICA. México, 2011. (3) M. Ding et al. Plant Dis. 95:357, 2011. (4) I. Mavrič et al. Plant Dis. 85:12, 2001.


Current treatment of hypoparathyroidism: Theory versus reality waiting guidelines for children and adolescents.
The diagnosis of hypoparathyroidism(HPT)is readily made in the presence of hypocalcemia with markedly reduced or absent parathormone (PTH) levels. Currently available treatments for HPT include high dose vitamin D (ergocalciferol, D2 and cholecalciferol, D3) or, the active metabolite dihydroxy vitamin D (calcitriol), in addition to calcium supplements.This regimen, if not well monitored, can lead to hypercalciuria, as PTH deficiency impairs renal calcium reabsorption. Thus the goal of treatment, is to maintain serum calcium at the low end of the normal range. Undertreatment can cause symptomatic hypocalcemia, while overtreatment hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. At present, there is no consensus on the management of HPT in children and adolescents and only few studies are available on the long term outcome of patients with recombinant HPT treatment. The purpose of this article is to review, in a comprehensive manner, the major aspects of HPT management in children and adolescents waiting for authoritative guidelines for the treatment of HPT in this group of patients. Further research, addressing specific questions for this population are urgently needed to improve long-term safety of patients. Educational interventions are also needed for professionals, parents and patients to enable them to improve knowledge, quality of life and effective management care at home.


Epidermal growth factor receptor monoclonal antibodies inhibit the growth of lung cancer cell lines.
The ability of monoclonal antibody (MAb 108), an immunoglobulin G (IgG)2a against the epidermal growth factor receptor (EGF-R), to interact with lung cancer cell lines was investigated. 125I-EGF bound with high affinity to non-small-cell lung cancer (NSCLC) cells, and MAb 108 inhibited specific binding of nine NSCLC cell lines in a dose-dependent manner (IC50 = 0.3-3 micrograms per ml). 125I-MAb 108 bound with high affinity (kd = 2 nM) to a single class of sites (Bmax = 70,000 per cell) using NSCLC neuroendocrine cell line NCI-H460. Specific 125I-MAb 108 binding was inhibited with high affinity by MAb 108 but not by a control antibody IgG using large-cell carcinoma cell line NCI-H1299. 125I-MAb 108 binding was not internalized at 37 degrees C using NSCLC neuroendocrine cell line NCI-H460 and adenocarcinoma cell line NCI-H23. Also, 1 microgram per ml of MAb 108 but not of a control IgG inhibited the clonal growth of NCI-H23 and squamous cell carcinoma cell line NCI-H157 in vitro. Also, MAb 108 inhibited xenograft formation of cell lines NCI-H460, NCI-H157, and NCI-H727 in nude mice in vivo. After a palpable tumor had formed using NCI-H460 cells, injection of 100 micrograms of MAb 108 (intraperitoneally three times weekly) inhibited xenograft volume in nude mice by approximately 50%. These data suggest that MAb 108 may interact with EGF receptors on lung cancer cell lines and inhibit NSCLC proliferation.


[Mental health care in times of corona: experiences of professionals with eHealth].
Due to the COVID-19 pandemic, most treatments in mental health care are provided through video calling. To poll what they think of remote care among 605 care providers of Arkin. We surveyed 605 professionals on their experiences. Enthusiasm for remote care was found predominantly among psychologists who worked in curative care. They reported practical benefits for the patient and for the process of care provision. Psychiatrists and clinical psychologists who provided care to patients with complex and/or chronic problems. They feared a deterioration in quality of care and a decline in their job satisfaction. Nurses were also critical, especially those who provided FACT and outreaching care. Their patients often lacked the resources or skills required to access digital care. This assessment of remote care was likely adversely affected by the corona measures. Employees were suddenly forced to alter their usual work habits and had not been optimally trained in the new method were more critical. Moreover, they were forced to work from home and lacked informal professional contact with colleagues. Nevertheless, professionals have a nuanced and predominantly positive opinion of video calling: it is not suitable for everyone or appropriate under all circumstances, but remote care is seen as a useful addition to the existing arsenal of treatment modalities.


Pulmonary lesions associated with sputum culture-positive actinomycetes: report of one case.
Pulmonary actinomycosis (PA) is a rare subacute or chronic infectious disease. As simple culture of Actinomyces in BAL, as with sputum, may represent colonization, the diagnosis of PA relies on pathological examination. The preferred treatment is long-term, high-dose penicillin. A 6-12-month-course of antibacterial treatment is the rule in extended PA, although the optimal duration of treatment has not been investigated through randomized trial. In this article, we report a case presented with slowly-progressing pulmonary cavitary lesions. Actinomyces odontolyticus was detected in sputum specimen harvested by tracheoscopy. The clinical diagnosis was PA, which gradually improved with prolonged treatment of penicillin and ornidazole. This is followed by a discussion of diagnosis and treatment, especially in terms of treatment.


Long-term clinical outcomes following en bloc resections for sacral chordomas and chondrosarcomas: a series of twenty consecutive patients.
Retrospective study of 20 consecutive patients who underwent en bloc tumor excision of sacral chordomas and chondrosarcomas. To evaluate the functional and oncological outcomes following en bloc tumor excision for sacral chordomas and chondrosarcomas. Chordomas and chondrosarcomas are 2 of the most common malignant primary tumors of the sacrum in adults. To date, few large clinical series with en bloc resection of these tumors exist. An institutional primary spine tumor surgical database was retrospective reviewed. Twenty consecutive patients with sacral chordomas and chondrosarcomas who underwent primary en bloc tumor excisions from 2002 to 2007 were included in the study. Surgical margin, perioperative complications, and postoperative functional status in these patients were analyzed. Disease-free survival following en bloc tumor excision was determined using the Kaplan-Meier method. The study cohort included 8 males and 12 females with an average age of 53.5 years and a man follow-up of 47.8 months. Wide or marginal en bloc resection was achieved in 14 patients. In 6 other patients, tumor was identified at the surgical margins, and they were considered to have contaminated/intralesional resections. The 30-day perioperative morbidities in this series included 1 death from pulmonary embolism and 9 wound complications. Forty percent of the patients had normal bladder and bowel functions after surgery, while 60% of the patients had partial or complete loss of bladder and bowel functions. All but 2 patients in this group remained ambulatory after the surgery. The mean disease-free survival for patients with wide or marginal en bloc tumor excisions was 51 months, but the mean disease-free survival was only 17.5 months for patients who had contaminated/intralesional resections. Wide or marginal en bloc excision of sacral chordoma and chondrosarcoma is associated with significant improvement in disease-free survival with acceptable perioperative morbidity rate.


Mitral valve repair in the elderly: operative risk for patients over 70 years of age is acceptable.
Mitral valve repair for degenerative disease is widely accepted. Because of low risk and excellent late outcomes, surgical intervention is recommended increasingly early when repair appears possible. The place of repair vis a vis continued medical therapy in the elderly, however, is less well defined as there are scant data on their surgical risk. We reviewed our recent results with mitral valvuloplasty for degenerative disease with attention to the influence of age. Thirty-day results of mitral valvuloplasty for degenerative disease between January 1996 and April 2000 were examined retrospectively. Patients with ischemic etiology were excluded. Results among those over age 70 years were compared with younger patients. Of 140 patients (78 men and 62 women) aged 27 to 91 (mean 62+/-13) years (44 gs;70 years of age), 61 underwent isolated mitral valvuloplasty, 71 mitral valvuloplasty and coronary artery bypass, and 8 mitral valvuloplasty with other procedures. By multivariate analysis preoperative cardiogenic shock (0.001), but not age, was as a risk factor for death. Among patients stratified by age gs; or <70, there were differences in atrial fibrillation (47.7% vs 29.2%, p=0.03), prolonged ventilation (31.8% vs 15.6%, p=0.03) and hospital stay (median 9.5, range 5-285 vs median 6.5, range 2-36, p=0.001), but not 30-day readmission (15.9% vs 22.9%) or death (5.2% vs 9.1%, p=0.49). Operative results for mitral valvuloplasty in the elderly are acceptable. Surgery should not be withheld on the basis of age alone.


Positron emission tomography and radioimmunotargeting--general aspects.
To optimize radioimmunotherapy, in vivo information on individual patients, such as radionuclide uptake, kinetics, metabolic patterns and optimal administration methods, is important. An overriding problem is to determine accurately the absorbed dose in the target organ as well as critical organs. Positron Emission Tomography (PET) is a superior technique to quantify regional kinetics in vivo with a spatial resolution better than 1 cm3 and a temporal resolution better than 10 s. However, target molecules often have distribution times of several hours to days. Conventional PET nuclides are not applicable and alternative positron-emitting nuclides with matching half-lives and with suitable labelling properties are thus necessary. Over many years we have systematically developed convenient production methods and labelling techniques of suitable positron nuclides, such as 110In(T(1/2) = 1.15 h), 86Y(T(1/2) = 14 h), 76Br(T(1/2) = 16 h) and 124I(T(1/2) = 4 days). 'Dose planning' can be done, for example, with 86Y- or 124I-labelled ligands before therapy, and 90Y- and 131I-labelled analogues and double-labelling, e.g. with a 86Y/90Y-labelled ligand, can be used to determine the true radioactivity integral from a pure beta-emitting nuclide. The usefulness of these techniques was demonstrated in animal and patient studies by halogen-labelled MAbs and EGF-dextran conjugates and peptides chelated with metal ions.


Dynamic contrast-enhanced CT for the assessment of tumour response in malignant pleural mesothelioma: a pilot study.
The aim of this pilot study was to investigate the utility of haemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans in the assessment of tumour response to treatment in malignant pleural mesothelioma (MPM) patients. The patient cohort included nine patients undergoing chemotherapy and five patients on observation. Each patient underwent two DCE-CT scans separated by approximately 2 months. The DCE-CT parameters of tissue blood flow (BF) and tissue blood volume (BV) were obtained within the dynamically imaged tumour. Mean relative changes in tumour DCE-CT parameters between scans were compared between the on-treatment and on-observation cohorts. DCE-CT parameter changes were correlated with relative change in tumour bulk evaluated according to the modified RECIST protocol. Differing trends in relative change in BF and BV between scans were found between the two patient groups (p = 0.19 and p = 0.06 for BF and BV, respectively). No significant rank correlations were found when comparing relative changes in DCE-CT parameters with relative change in tumour bulk. Differing trends in the relative change of BF and BV between patients on treatment and on observation indicate the potential of DCE-CT for the assessment of pharmacodynamic endpoints with respect to treatment in MPM. A future study with a larger patient cohort and unified treatment regimens should be undertaken to confirm the results of this pilot study. • CT-derived haemodynamic parameters show differing trends between malignant pleural mesothelioma patients on treatment and patients off treatment • Changes in haemodynamic parameters do not correlate with changes in tumour bulk as measured according to the modified RECIST protocol • Differing trends across the two patient groups indicate the potential sensitivity of DCE-CT to assess pharmacodynamic endpoints in the treatment of MPM.


Double trouble: two cases of dual adrenal pathologies in one adrenal mass.
Context Adrenal incidentalomas (AI) represent an increasingly common problem in modern endocrine practice. The diagnostic approach to AIs can be challenging and occasionally reveals surprising features. Here we describe two rare cases of complex adrenal lesions consisting of phaeochromocytomas with synchronous metastases from extra-adrenal primaries. Case descriptions Patient 1 - a 65-year-old gentleman with a newly diagnosed malignant melanoma was found to harbour an adrenal lesion with suspicious radiographic characteristics. Percutaneous adrenal biopsy was consistent with adrenocortical adenoma. After excision of the skin melanoma and regional lymphatic metastases, he was followed up without imaging. Three years later, he presented with abdominal discomfort and enlargement of his adrenal lesion, associated with high plasma metanephrines. Adrenalectomy revealed a mixed tumour consisting of a large phaeochromocytoma with an embedded melanoma metastasis in its core. Patient 2 - a 63-year-old lady with a history of NF-1-related phaeochromocytoma 20 years ago and previous breast cancer presented with a new adrenal lesion on the contralateral side. Plasma normetanephrine was markedly elevated. Elective adrenalectomy revealed an adrenal tumour consisting of chromaffin cells intermixed with breast carcinoma cells. Conclusions Adrenal incidentalomas require careful evaluation to exclude metastatic disease, especially in the context of a history of previous malignancy. Adrenal biopsy provides limited and potentially misleading information. Phaeochromocytomas are highly vascularised tumours that may function as a sieve, extracting and retaining irregularly shaped cancer cells, thereby yielding adrenal masses with intriguing dual pathology. Learning points: Adrenal incidentalomas require careful evaluation focused on exclusion of underlying hormone excess and malignant pathology. Adrenal biopsy can be misleading and should only be considered in select cases. Phaeochromocytomas harbouring intratumoural metastases from other, extra-adrenal primary malignancies represent rare pathological entities that highlight the complexities that can be presented by adrenal tumours.


Can quality improvement be optional?
Comments on the article by J. C. Fortney et al. (see record 2018-24946-001) describing their relatively unsuccessful efforts to implement improved care for patients with complex mood disorders in safety net clinics. It is unusual for scientists to submit papers describing their unsuccessful studies and even more unusual for journals to publish them. More importantly, Fortney and this journal have provided us with an unusually detailed and thoughtful description of many of the factors that may have contributed to this result. Few studies actually provide this close a look at what was done to implement the desired changes. (PsycINFO Database Record


'Cap myopathy': case report of a family.
We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.


Stochastic optimal control methods for investigating the power of morphological computation.
One key idea behind morphological computation is that many difficulties of a control problem can be absorbed by the morphology of a robot. The performance of the controlled system naturally depends on the control architecture and on the morphology of the robot. Because of this strong coupling, most of the impressive applications in morphological computation typically apply minimalistic control architectures. Ideally, adapting the morphology of the plant and optimizing the control law interact so that finally, optimal physical properties of the system and optimal control laws emerge. As a first step toward this vision, we apply optimal control methods for investigating the power of morphological computation. We use a probabilistic optimal control method to acquire control laws, given the current morphology. We show that by changing the morphology of our robot, control problems can be simplified, resulting in optimal controllers with reduced complexity and higher performance. This concept is evaluated on a compliant four-link model of a humanoid robot, which has to keep balance in the presence of external pushes.


The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma.
Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.


What you see is not what you get: how sampling affects macroscopic features of biological networks.
We use mathematical methods from the theory of tailored random graphs to study systematically the effects of sampling on topological features of large biological signalling networks. Our aim in doing so is to increase our quantitative understanding of the relation between true biological networks and the imperfect and often biased samples of these networks that are reported in public data repositories and used by biomedical scientists. We derive exact explicit formulae for degree distributions and degree correlation kernels of sampled networks, in terms of the degree distributions and degree correlation kernels of the underlying true network, for a broad family of sampling protocols that include random and connectivity-dependent node and/or link undersampling as well as random and connectivity-dependent link oversampling. Our predictions are in excellent agreement with numerical simulations.


Analysis of S. pombe SIN protein association to the SPB reveals two genetically separable states of the SIN.
The Schizosaccharomyces pombe septation initiation network (SIN) regulates cytokinesis, and asymmetric association of SIN proteins with the mitotic spindle pole bodies (SPBs) is important for its regulation. Here, we have used semi-automated image analysis to study SIN proteins in large numbers of wild-type and mutant cells. Our principal conclusions are: first, that the association of Cdc7p with the SPBs in early mitosis is frequently asymmetric, with a bias in favour of the new SPB; second, that the early association of Cdc7p-GFP to the SPB depends on Plo1p but not Spg1p, and is unaffected by mutations that influence its asymmetry in anaphase; third, that Cdc7p asymmetry in anaphase B is delayed by Pom1p and by activation of the spindle assembly checkpoint, and is promoted by Rad24p; and fourth, that the length of the spindle, expressed as a fraction of the length of the cell, at which Cdc7p becomes asymmetric is similar in cells dividing at different sizes. These data reveal that multiple regulatory mechanisms control the SIN in mitosis and lead us to propose a two-state model to describe the SIN.


Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone.
We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL.


Patients With Type 2 Diabetes Have an Increased Demand for Pacemaker Treatment: A Comparison With Age- and Sex-Matched Control Subjects From the General Population.
Patients with type 2 diabetes have an increased risk for cardiovascular disease, including arrhythmias. The prevalence of bradyarrhythmia and the subsequent need for treatment with pacemakers (PMs) is less well explored in a contemporary patient population. The current study explores 1) whether patients with type 2 diabetes have an increased demand for PM implantation compared with an age- and sex-matched control population without diabetes and 2) patient characteristics associated with an increased demand for receiving a PM. In this population-matched registry study, a total of 416,247 patients with type 2 diabetes from the Swedish National Diabetes Registry and 2,081,235 age- and sex-matched control subjects selected from the general population were included between 1 January 1998 and 31 December 2012 and followed until 31 December 2013. Mean follow-up time was 7 years. Cox proportional hazards regression analyses were performed to estimate the demand of PM treatment and the factors identifying patients with such demand. Type 2 diabetes was associated with an increased need of PM treatment (hazard ratio 1.65 [95% CI 1.60-1.69]; P < 0.0001), which remained (1.56 [1.51-1.60]; P < 0.0001) after adjustments for age, sex, educational level, marital status, country of birth, and coronary heart disease. Risk factors for receiving a PM included increasing age, HbA1c, BMI, diabetes duration, and lipid- and blood pressure-lowering medication. The need for PM treatment is higher in patients with type 2 diabetes than in matched population-based control subjects. Age, diabetes duration, and HbA1c seem to be risk factors for PM treatment.


Pain in patients with multiple sclerosis.
This study aims to identify the factors associated with pain and neuropathic pain (NP) in patients with multiple sclerosis (MS) and to determine the relationship between pain and NP with disability, functionality, activities of daily living, fatigue, mood, and quality of life (QoL). Between July 2017 and October 2017, a total of 100 adult patients with MS (18 males, 82 females; mean age: 35.3±9.9 years; range, 19 to 71 years) were included. All patients were evaluated in terms of pain and NP. Patients with and without pain, and patients with and without NP were compared in terms of sociodemographic characteristics, disease data, disability, functionality, daily living activities, fatigue severity, mood, and QoL using various scales. A total of 62% of the patients had pain. Pain was found to be associated with low education level (p=0.014), increased fatigue (p<0.001), depressive mood (p<0.001) and lower QoL (p<0.001). A total of 29.03% of patients with pain had NP. Patients with NP had a greater pain intensity (p<0.001) and fatigue (p=0.002) and lower QoL (p=0.011). The number of patients who received the correct treatment for their symptoms was low. Pain and NP should be better investigated and treated by physicians, as these symptoms are common in MS and adversely affect the QoL and social relations of affected patients and reduce their productivity.


Determining riverine sediment storage mechanisms of biologically reactive phosphorus in situ using DGT.
Phosphorus (P) is the main reason many surficial water bodies in the UK are currently failing to meet the chemical standards set by the Water Framework Directive (WFD). This work focuses on the role of sediments in the upper reaches of the River Taw in the South West of the UK. Point and diffuse sources of P have been identified as well as a number of mitigation measures applied or planned to address the issues. However, it is unknown what effect these sources have had on the river's sediments and how they will react to diminishing inputs of P into the water column in the future. The diffusive gradient in thin-films (DGT) method is utilised in situ to quantify and identify labile, potentially bioavailable P fluxes and potential storage mechanisms at sites of known diffuse and point P inputs. In the vicinity of a heavily contaminated point source, data present here shows that sediments are still acting as a sink. The proposed mechanism for this is the formation of a 'calcium cap' which provides a geochemical barrier between the sediment and overlying water to prevent loss of labile P. The strong correlation between calcium and total P under most circumstances supports this hypothesis. This conclusion provides some confidence that even though P concentrations in some sediments are significantly elevated, mobility between the sediment and overlying water is restricted. In the context of routine monitoring against WFD targets, the molybdenum blue method generally employed to determine soluble reactive phosphorus was shown to not be equivalent to the DGT labile P pool, especially at pristine or moderately point/diffuse influenced sites. This is likely due to desorption of weakly bound P from colloids, which is unavailable to DGT devices. These results have the potential to be scaled up to the full catchment or other catchments which exhibit similar physical and chemical sediment composition and provide a stronger foundation for management and target setting than current monitoring approaches.


Evaluation and management of skeletal health in celiac disease: position statement.
To review the evaluation and management of skeletal health in patients with celiac disease (CD), and to make recommendations on screening, diagnosis, treatment and follow-up of low bone mineral density (BMD) in CD patients. A multidisciplinary team developed clinically relevant questions for review. An electronic search of the literature was conducted using the MEDLINE and EMBASE databases from 1996 to 2010. All original studies, reviews and guidelines, both pediatric and adult, were included. A document summarizing the results of the review and proposed recommendations was prepared and underwent multiple revisions until consensus was reached. At diagnosis, approximately one-third of adult CD patients have osteoporosis, one-third have osteopenia and one-third have normal BMD. Children with CD have low bone mass at diagnosis. Adult and pediatric CD patients are at increased risk of fractures. For adults, serum calcium, albumin, 25(OH) vitamin D3, parathyroid hormone and 24 h urine calcium testing should be performed at diagnosis; patients with 'classic' CD and those at risk for osteoporosis should undergo a dual x-ray absorptiometry scan. An abnormal baseline dual x-ray absorptiometry scan should be repeated one to two years after initiation of a gluten-free diet (GFD). For children, BMD should be assessed one year after diagnosis if GFD adherence is not strict. A GFD is the most important treatment for bone loss. Supplemental antiresorptives may be justified in those who remain at high fracture risk (eg, postmenopausal women, older men) after implementation of a GFD. Current evidence does not support the screening of all CD patients for low BMD at diagnosis. Follow-up BMD assessment should be performed one to two years after initiation of a GFD.


Chemotherapy and survival for patients with multiple myeloma: findings from a large nationwide and population-based cohort.
To assess the patterns of chemotherapy use for patients with multiple myeloma and to determine if chemotherapy is effective in prolonging survival outside the clinical trial settings. We studied a nationwide and population-based retrospective cohort of 4902 patients > or =65 years of age with stage II or III multiple myeloma from 1992 to 1999, identified from the Surveillance, Epidemiology, and End-Results-Medicare data. Multivariate logistic regression was used to estimate the odds ratio of receiving chemotherapy and Cox proportional hazard model was used to estimate the hazard ratio of mortality associated with chemotherapy. Of 4902 patients with stage II or III multiple myeloma, 52.0% received chemotherapy during the course of the disease. The receipt of chemotherapy decreased significantly with age from 65.7% in the 65- to 69-year age group to 34.3% in those > or =80 years. Blacks (47.6%) were less likely to receive chemotherapy than whites (52.8%). Use of chemotherapy decreased significantly with comorbidity scores and increased over time. Risk of all-cause mortality was significantly reduced in patients who received chemotherapy compared with those who did not (adjusted hazard ratio = 0.65; 95% confidence interval = 0.61-0.69). A similar pattern as observed for myeloma-specific mortality (0.61; 0.56-0.67). Survival benefit increased with increasing cycles of chemotherapy (P < 0.001 for trend) and was significant across different age groups, gender, ethnic groups, and comorbidity scores. Chemotherapy was significantly associated with increased survival in patients with multiple myeloma outside the clinical trial settings. This survival benefit was significant across different groups by age, gender, race, and comorbidity. A substantial number of patients with multiple myeloma did not receive chemotherapy.


Understanding the origins of UV-induced recombination through manipulation of sister chromatid cohesion.
Ultraviolet light (UV) can provoke genome instability, partly through its ability to induce homologous recombination (HR). However, the mechanism(s) of UV-induced recombination is poorly understood. Although double-strand breaks (DSBs) have been invoked, there is little evidence for their generation by UV. Alternatively, single-strand DNA lesions that stall replication forks could provoke recombination. Recent findings suggest efficient initiation of UV-induced recombination in G1 through processing of closely spaced single-strand lesions to DSBs. However, other scenarios are possible, since the recombination initiated in G1 can be completed in the following stages of the cell cycle. We developed a system that could address UV-induced recombination events that start and finish in G2 by manipulating the activity of the sister chromatid cohesion complex. Here we show that sister-chromatid cohesion suppresses UV-induced recombination events that are initiated and resolved in G2. By comparing recombination frequencies and survival between UV and ionizing radiation, we conclude that a substantial portion of UV-induced recombination occurs through DSBs. This notion is supported by a direct physical observation of UV-induced DSBs that are dependent on nucleotide excision repair. However, a significant role of nonDSB intermediates in UV-induced recombination cannot be excluded.


Comparative Analyses of Transcriptional Profiles in Mouse Organs Using a Pneumonic Plague Model after Infection with Wild-Type Yersinia pestis CO92 and Its Braun Lipoprotein Mutant.
We employed Murine GeneChips to delineate the global transcriptional profiles of the livers, lungs, and spleens in a mouse pneumonic plague infection model with wild-type (WT) Y. pestis CO92 and its Braun lipoprotein (Deltalpp) mutant with reduced virulence. These organs showed differential transcriptional responses to infection with WT Y. pestis, but the overall host functional processes affected were similar across all three tissues. Gene expression alterations were found in inflammation, cytokine signaling, and apoptotic cell death-associated genes. Comparison of WT and Deltalpp mutant-infected mice indicated significant overlap in lipopolysaccharide- (LPS-) associated gene expression, but the absence of Lpp perturbed host cell signaling at critical regulatory junctions resulting in altered immune response and possibly host cell apoptosis. We generated a putative signaling pathway including major inflammatory components that could account for the synergistic action of LPS and Lpp and provided the mechanistic basis of attenuation caused by deletion of the lpp gene from Y. pestis in a mouse model of pneumonic plague.


Real-time functional characterization of cationic amino acid transporters using a new FRET sensor.
L-arginine is a semi-essential amino acid that serves as precursor for the production of urea, nitric oxide (NO), polyamines, and other biologically important metabolites. Hence, a fast and reliable assessment of its intracellular concentration changes is highly desirable. Here, we report on a genetically encoded Förster resonance energy transfer (FRET)-based arginine nanosensor that employs the arginine repressor/activator ahrC gene from Bacillus subtilis. This new nanosensor was expressed in HEK293T cells, and experiments with cell lysate showed that it binds L-arginine with high specificity and with a K d of ∼177 μM. Live imaging experiments showed that the nanosensor was expressed throughout the cytoplasm and displayed a half maximal FRET increase at an extracellular L-arginine concentration of ∼22 μM. By expressing the nanosensor together with SLC7A1, SLC7A2B, or SLC7A3 cationic amino acid transporters (CAT1-3), it was shown that L-arginine was imported at a similar rate via SLC7A1 and SLC7A2B and slower via SLC7A3. In contrast, upon withdrawal of extracellular L-arginine, intracellular levels decreased as fast in SLC7A3-expressing cells compared with SLC7A1, but the efflux was slower via SLC7A2B. SLC7A4 (CAT4) could not be convincingly shown to transport L-arginine. We also demonstrated the impact of membrane potential on L-arginine transport and showed that physiological concentrations of symmetrical and asymmetrical dimethylarginine do not significantly interfere with L-arginine transport through SLC7A1. Our results demonstrate that the FRET nanosensor can be used to assess L-arginine transport through plasma membrane in real time.


Support workers in intermediate care.
Despite the proliferation of support worker roles in the UK, little is known about their actual numbers, employment conditions or levels of training. Intermediate care services appear to be an important employer of support workers, but the diversity of intermediate care services makes the task of understanding support worker roles even more complex. This paper presents data from 33 services which were involved in an NHS Modernisation Agency's Changing Workforce Programme project, the Accelerated Development Programme for Support Workers in Intermediate Care in England. Within this project, the main employers of support workers were primary care trusts and/or social services. Participating intermediate care teams were involved in admission avoidance, assisted discharge and reablement, or combinations of these services, and the majority of care was provided in the patient's own home. The 33 services employed 794 support workers and 368 professionally qualified staff. The mean ratio of professionally qualified staff to support workers was 0.95 (range = 0-4.9, SD = 1.05). Support worker roles included multidisciplinary working, meeting rehabilitation needs, providing personal care and enablement. Team leaders included nurses, social workers, physiotherapists, professional managers, home carers and support workers. The most commonly reported sources of support worker training were National Vocational Qualifications and in-house training. In 80% of the services, at least half of the support workers had a qualification. Three models of supervision emerged across the services: the allocation of a mentor; team supervision; and formal and informal line management. These findings illustrate the diversity of employment of support workers in intermediate care. The variations in training, supervision and skill mix have implications for clinical governance and support worker regulation. The employment of support worker staff jointly across health and social care raises cross-boundary issues around employment contracts and pay.


Cytotoxicity of and DNA adduct formation by ellipticine in human U87MG glioblastoma cancer cells.
Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of action with promising brain tumor specificity. This anticancer agent should be considered a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its cytochrome P450 (CYP) - and/or peroxidase-mediated activation to species forming covalent DNA adducts. Ellipticine can also act as an inhibitor or inducer of biotransformation enzymes, thereby modulating its own metabolism leading to its genotoxic and pharmacological effects. The toxicity of ellipticine to U87MG glioblastoma cells and mechanisms of its action to these cells are aims of this study. Ellipticine metabolites formed in U87MG cells were analyzed using HPLC. Covalent DNA modifications by ellipticine were detected by 32P-postlabeling. CYP enzyme expression was examined by QPCR and Western blot. U87MG glioblastoma cell proliferation was efficiently inhibited by ellipticine. This effect might be associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by 13-hydroxy- and 12-hydroxyellipticine, the ellipticine metabolites generated by CYP1A1, 1B1 and 3A4, lactoperoxidase and cyclooxygenase 1, the enzymes expressed in U87MG cells. Moreover, by inducing CYP1B1, 3A4 and 1A1 enzymes in U87MG cells, ellipticine increases its own enzymatic activation, thereby enhancing its own genotoxic and pharmacological potential in these cells. Ellipticine concentration used for U87MG cell treatment is extremely important for its pharmacological effects, as its metabolite profiles differed substantially predicting ellipticine to be either detoxified or activated. The results found in this study are the first report showing cytotoxicity and DNA adduct formation by ellipticine in glioblastomas.


Decision-making theories and their usefulness to the midwifery profession both in terms of midwifery practice and the education of midwives.
What are the strengths and limitations of existing Decision-Making Theories as a basis for guiding best practice clinical decision-making within a framework of midwifery philosophy? Each theory is compared in relation with how well they provide a teachable framework for midwifery clinical reasoning that is consistent with midwifery philosophy. Hypothetico-Deductive Theory, from which medical clinical reasoning is based; intuitive decision-making; Dual Processing Theory; The International Confederation of Midwives Clinical Decision-Making Framework; Australian Nursing and Midwifery Council Midwifery Practice Decisions Flowchart and Midwifery Practice. Best practice midwifery clinical Decision-Making Theory needs to give guidance about: (i) effective use of cognitive reasoning processes; (ii) how to include contextual and emotional factors; (iii) how to include the interests of the baby as an integral part of the woman; (iv) decision-making in partnership with woman; and (v) how to recognize/respond to clinical situations outside the midwife's legal/personal scope of practice. No existing Decision-Making Theory meets the needs of midwifery. Medical clinical reasoning has a good contribution to make in terms of cognitive reasoning processes. Two limitations of medical clinical reasoning are its reductionistic focus and privileging of reason to the exclusion of emotional and contextual factors. Hypothetico-deductive clinical reasoning is a necessary but insufficient condition for best practice clinical decision-making in midwifery.


Extending the study of visual attention to a multisensory world (Charles W. Eriksen Special Issue).
Charles W. Eriksen (1923-2018), long-time editor of Perception & Psychophysics (1971-1993) - the precursor to the present journal - undoubtedly made a profound contribution to the study of selective attention in the visual modality. Working primarily with neurologically normal adults, his early research provided both theoretical accounts for behavioral phenomena as well as robust experimental tasks, including the well-known Eriksen flanker task. The latter paradigm has been used and adapted by many researchers over the subsequent decades. While Eriksen's research interests were primarily focused on situations of unimodal visual spatially selective attention, here I review evidence from those studies that have attempted to extend Eriksen's general approach to non-visual (i.e., auditory and tactile) selection and the more realistic situations of multisensory spatial attentional selection.


Anti-staphylococcal activity of C-methyl flavanones from propolis of Australian stingless bees (Tetragonula carbonaria) and fruit resins of Corymbia torelliana (Myrtaceae).
Propolis of Australian stingless bees (Tetragonula carbonaria, Meliponini) originating from Corymbia torelliana (Myrtaceae) fruit resins was tested for its antimicrobial activities as well as its flavonoid contents. This study aimed at the isolation, structural elucidation and antibacterial testing of flavanones of C. torelliana fruit resins that are incorporated into stingless bee propolis. Flavanones of this study were elucidated by spectroscopic and spectrometric methods including UV, 1D and 2D NMR, EI-MS, ESI-MS and HR-MS. The results indicated known C-methylated flavanones namely, 1 (2S)-cryptostrobin, its regioisomer 2 (2S)- stroboponin, 3 (2S)- cryptostrobin 7-methyl ether, and 6 (2S)- desmethoxymatteucinol, and known flavanones 4 (2S)- pinostrobin and 5 (2S)- pinocembrin as markers for C. torelliana fruit resins and one propolis type. Ethanolic preparations of propolis were shown to be active against Staphylococcus aureus (ATCC 25923) and to a lesser extent against Pseudomonas aeruginosa (ATCC 27853). C. torelliana flavanones inhibited the growth of S. aureus therefore contributing to the antibacterial effects observed for Australian stingless bee propolis extracts.


Predictors of reoperation following operative management of fractures of the tibial shaft.
Accurate prediction of likelihood of reoperation in patients with tibial shaft fractures would facilitate optimal management. Previous studies were limited by small sample sizes and noncomprehensive examination of possible risk factors. We conducted an observational study to determine which prognostic factors were associated with an increased risk of reoperation following operative treatment in a heterogeneous population of patients with tibial shaft fractures. Retrospective observational study. Level 1 trauma center. We identified 200 patients with tibial shaft fractures from two university-affiliated centers. Two reviewers independently abstracted data regarding 20 possible prognostic variables, reviewed preoperative and postoperative radiographs, and documented reoperations (defined as any surgical procedure </=1 year after the initial surgery that was aimed specifically at achieving bony union of the fracture, including bone grafts, implant exchanges, or débridement for infections). We chose a Cox proportion hazards model to conduct a survival analysis for time to reoperation and constructed a multivariable model to estimate the relative risk of reoperation and associated 95%confidence interval (CI) for each predictor variable. Time to reoperation following the initial surgery. Complete follow-up information was available for 192 of 200 (96%) patients. Three variables predicted reoperation: the presence of an open fracture wound (relative risk 4.32, 95% CI 1.76 to 11.26), lack of cortical continuity between the fracture ends following fixation (relative risk 8.33, 95% CI 3.03 to 25.0), and the presence of a transverse fracture (relative risk 20.0, 95% CI 4.34 to 142.86). We identified a set of three simple prognostic variables (open fracture, transverse fracture, and postoperative fracture gap) that can assist surgeons in predicting reoperation following operative treatment of tibial shaft fractures.


Prospective study of tricuspid valve regurgitation associated with permanent leads in patients undergoing cardiac rhythm device implantation: Background, rationale, and design.
Given the increasing numbers of cardiac device implantations worldwide, it is important to determine whether permanent endocardial leads across the tricuspid valve can promote tricuspid regurgitation (TR). Virtually all current data is retrospective, and indicates a signal of TR being increased after permanent lead implantation. However, the precise incidence of moderate or greater TR post-procedure, the exact mechanisms (mechanical, traumatic, functional), and the hemodynamic burden and clinical effects of this putative increase in TR, remain uncertain. We have therefore designed a multicenter, international, prospective study of 300 consecutive patients (recruitment completed, baseline data presented) who will undergo echocardiography and clinical assessment prior to, and at 1-year post device insertion. This prospective study will help determine whether cardiac device-associated TR is real, what are its potential mechanisms, and whether it has an important clinical impact on cardiac device patients.


The Use of Sex-Specific Factors in the Assessment of Women's Cardiovascular Risk.
Cardiovascular disease (CVD) is the leading cause of death among women in the United States. As compared with men, women are less likely to be diagnosed appropriately, receive preventive care, or be treated aggressively for CVD. Sex differences between men and women have allowed for the identification of CVD risk factors and risk markers that are unique to women. The 2018 American Heart Association/American College of Cardiology Multi-Society cholesterol guideline and 2019 American College of Cardiology/American Heart Association guideline on the primary prevention of CVD introduced the concept of risk-enhancing factors that are specific to women and are associated with an increased risk of incident atherosclerotic CVD in women. These factors, if present, would favor more intensified lifestyle interventions and consideration of initiation or intensification of statin therapy for primary prevention to mitigate the increased risk. In this primer, we highlight sex-specific CVD risk factors in women, stress the importance of eliciting a thorough obstetrical and gynecological history during cardiovascular risk assessment, and provide a framework for how to initiate appropriate preventive measures when sex-specific risk factors are present.


Standards for the Characterization of Endurance in Resistive Switching Devices.
Resistive switching (RS) devices are emerging electronic components that could have applications in multiple types of integrated circuits, including electronic memories, true random number generators, radiofrequency switches, neuromorphic vision sensors, and artificial neural networks. The main factor hindering the massive employment of RS devices in commercial circuits is related to variability and reliability issues, which are usually evaluated through switching endurance tests. However, we note that most studies that claimed high endurances >106 cycles were based on resistance versus cycle plots that contain very few data points (in many cases even <20), and which are collected in only one device. We recommend not to use such a characterization method because it is highly inaccurate and unreliable (i.e., it cannot reliably demonstrate that the device effectively switches in every cycle and it ignores cycle-to-cycle and device-to-device variability). This has created a blurry vision of the real performance of RS devices and in many cases has exaggerated their potential. This article proposes and describes a method for the correct characterization of switching endurance in RS devices; this method aims to construct endurance plots showing one data point per cycle and resistive state and combine data from multiple devices. Adopting this recommended method should result in more reliable literature in the field of RS technologies, which should accelerate their integration in commercial products.


Awareness of Antibiotics and Antibiotic Resistance in a Rural District of Ha Nam Province, Vietnam: A Cross-Sectional Survey.
Low awareness of antibiotics and antibiotic resistance may lead to inappropriate antibiotic use and contribute to the problem of antibiotic resistance. This study explored levels and determinants of antibiotic awareness in a rural community in northern Vietnam, through a cross-sectional survey of 324 households in one commune of Ha Nam Province. Awareness and knowledge of antibiotics and antibiotic resistance and determinants were evaluated using structured questionnaires. Most respondents (232/323 (71.8%)) had heard of antibiotics, but fewer could name any antibiotic (68/323 (21.1%)) or had heard of antibiotic resistance (57/322 (17.7%)). In adjusted regression models, antibiotic awareness was lower among those who lived further from health facilities (Odds Ratio (OR): 0.08; 95% Confidence Interval (CI): 0.04-0.19) but higher among those who used interpersonal sources for health information (OR: 4.06; 95% CI: 1.32-12.46). Antibiotic resistance awareness was lower among those who used private providers or pharmacies as their usual health facility (OR: 0.14; 95% CI: 0.05-0.44) but higher among those with medical insurance (OR: 3.70; 95% CI: 1.06-12.96) and those with high media use frequency (OR: 9.54; 95% CI: 2.39-38.07). Awareness of Antimicrobial Resistance (AMR) was also higher among those who sought health information from official sources (OR: 3.88; 95% CI: 1.01-14.86) or had overall high levels of health information seeking (OR: 12.85; 95% CI: 1.63-101.1). In conclusion, communication interventions need to target frequently used media platforms, such as television, as well as key health information providers, such as health workers, as channels for increasing knowledge and changing community antibiotic use behaviour.


Determination of certain bacterial groups in gut microbiota and endotoxin levels in patients with nonalcoholic steatohepatitis.
In recent years, the role of the gut microbiota has emerged in several diseases. Herein we aimed to determine the fecal microbiota, endotoxin levels, and inflammation markers in patients with nonalcoholic steatohepatitis (NASH) and healthy controls. A total of 46 NASH patients and 38 healthy controls were included. NASH patients were diagnosed according to the steatosis, activity, and fibrosis score/fatty liver inhibition of progression algorithm. 16S rRNA gene-targeted specific primers were used for quantification of certain bacterial groups, and a plasmid library was constructed and sequenced in order to determine dominant Lactobacillus and Bifidobacterium members in patients and controls. Significantly decreased Akkermansia muciniphila and increased Enterobacteriaceae levels were determined in patients compared to healthy controls even after adjusting for the body mass index (BMI) and age. Patients with ≥F2 fibrosis had significantly higher Enterobacteriaceae levels compared to F0-F1 fibrosis. Serum endotoxin and high-sensitivity C-reactive protein levels were significantly higher in patients group. According to the sequencing results, L. reuteri, which was one of the dominant Lactobacillus species in the patient group, could not be detected in healthy controls. Bifidobacterium infantis was found in the patients' feces but not in the controls. We demonstrated a BMI and age-independent association between the presence of NASH and levels of A. muciniphila and Enterobacteriaceae as well as increased endotoxin levels. L. reuteri was abundant in the patient group, suggesting that dominant Lactobacillus species should be considered before probiotic treatments.


Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling.
Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.


Trends and variation in incidence, surgical treatment, and repeat surgery of proximal humeral fractures in the elderly.
the treatment of proximal humeral fractures in the elderly remains controversial. Options include nonoperative treatment, open reduction with internal fixation (ORIF), and hemiarthroplasty. Locking plate technology has expanded the indications for ORIF for certain fracture types in osteoporotic bone. This study was performed to characterize the incidence, treatment, and revision surgery of proximal humeral fractures according to geographic region both before (1999 to 2000) and after (2004 to 2005) the introduction of locking plates. we used a 20% sample of Medicare Part-B data and the Medicare denominator file for the years 1998 to 2006. Proximal humeral fractures were identified by Common Procedural Terminology codes for treatment, categorized as nonoperative, ORIF, or hemiarthroplasty. Geographic variation in treatment type was determined with use of 306 hospital referral regions. Odds ratios for revision surgery were calculated by the need for repeat surgery within one year of the index procedure. Rates were adjusted for age, sex, race, and comorbidities. there were 14,774 proximal humeral fractures in the 20% sample from 1999 to 2000 (an estimated total of 73,870 fractures) and 16,138 fractures in the sample from 2004 to 2005 (an estimated total of 80,690 fractures). The overall age, sex, and race-adjusted incidence of proximal humeral fractures was unchanged from 1999 to 2005 (2.47 vs. 2.48 per 1000 Medicare beneficiaries; p = 0.992). However, the absolute rate of surgically managed proximal humeral fractures rose 3.2 percentage points from 12.5% to 15.7%, a relative increase of 25.6% (p < 0.0001). The relative increase in the percentage of fractures treated with ORIF was 28.5% (p < 0.0001), while the percentage of fractures treated with hemiarthroplasty increased 19.6% (p < 0.0001). There were large regional variations in the proportion treated surgically (range, 0% to 68.18%). The rates of repeat surgery were significantly higher in 2004 to 2005 compared with 1999 to 2000 (odds ratio = 1.47, p = 0.043). although the incidence of proximal humeral fractures in the elderly did not change from 1999 to 2005, the rate of surgical treatment increased significantly. The marked regional variation in the rates of surgical treatment highlights the need for better consensus regarding optimal treatment of proximal humeral fractures. Additional research is needed to help to determine which fractures are best treated operatively in order to maximize outcome and minimize the need for revision surgery. therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.


Emergency surgery for acute diverticulitis: which operation? A National Surgical Quality Improvement Program study.
The optimal surgical management of acute diverticulitis is still a controversial and unresolved issue. While the Hartmann's procedure (`) is the most commonly performed operation, primary anastomosis (PA), with or without proximal diversion, has also been used with increasing frequency. This is a National Surgical Quality Improvement Program database study including all patients requiring emergency surgery for acute diverticulitis. Three operative approaches were analyzed: HP, colectomy with PA, and colectomy with PA with proximal diversion (PAPD). Mortality and postoperative outcomes were compared between the three groups using a logistical regression model. There were 1,314 patients who required emergent operation for acute diverticulitis, 75.4% underwent HP, 21.7% underwent PA, and 2.9% underwent PAPD. Thirty-day mortality was 7.3%, 4.6%, and 1.6% for HP, PA, and PAPD respectively (p = 0.163), while surgical site infections occurred in 19.7%, 17.9%, and 13.2%, respectively (p = 0.59). After multivariable analysis adjusting for age, alcohol consumption, comorbidities, steroid use, preoperative laboratory values, hemorrhage at admission and laparoscopic surgery, the adjusted odds ratio for 30-day mortality comparing PA with HP was 0.77 (95% confidence interval [CI], 0.38-1.56; p = 0.465), 0.47 (95% CI, 0.06-3.74; p = 0.479) comparing PAPD with HP, and 1.62 (95% CI, 0.19-13.78; p = 0.658) comparing PA with PAPD. In addition, the three groups did not have significantly different adjusted odds ratio for the development of surgical infectious complications, acute kidney injury, cardiovascular incidents, or venous thromboembolism after surgery. Resection and PA in patients undergoing an emergency operation for acute diverticulitis is a safe alternative to the HP, with no significant difference in mortality or postoperative surgical site infections. Therapeutic study, level IV.


Domain organization and biochemical features of Sulfolobus solfataricus DNA polymerase.
DNA polymerase from Sulfolobus solfataricus, strain MT4 (Sso DNA pol), was one of the first archaeal DNA polymerases to be isolated and characterized. Its encoding gene was cloned and sequenced, indicating that Sso DNA pol belongs to family B of DNA polymerases. By limited proteolysis experiments carried out on the recombinant homogeneous protein, we were able to demonstrate that the enzyme has a modular organization of its associated catalytic functions (DNA polymerase and 3'-5' exonuclease). Indeed, the synthetic function was ascribed to the enzyme C-terminal portion, whereas the N-terminal half was found to be responsible for the exonucleolytic activity. In addition, partial proteolysis studies were utilized to map conformational changes on DNA binding by comparing the cleavage map in the absence or presence of nucleic acid ligands. This analysis allowed us to identify two segments of the Sso DNA pol amino acid chain affected by structural modifications following nucleic acid binding: region 1 and region 2, in the middle and at the C-terminal end of the protein chain, respectively. Site-directed mutagenesis studies will be performed to better investigate the role of these two protein segments in DNA substrate interaction.


Phosphorescent platinum(II) complexes derived from multifunctional chromophores: synthesis, structures, photophysics, and electroluminescence.
The synthesis and structural, photophysical, electrochemical, and electroluminescent properties of a novel class of trifunctional Pt(II) cyclometalated complexes are reported in which the hole-transporting triarylamine, electron-transporting oxadiazole, and electroluminescent metal components are integrated into a single molecule. These neutral metal chelates display good thermal stability (>250 degrees C under N2) and morphological stability. All of them exhibit intense ligand-centered fluorescence and phosphorescence in fluid solutions at room temperature, but the emission spectra become largely dominated by triplet emission bands in CH2Cl2 glass at 77 K. Substituents with different electronic properties were introduced into the bipolar cyclometalating ligands to fine-tune the absorption and emissive characteristics of the compounds, and the results were correlated with theoretical calculations using density functional theory. A comparison of the photophysics and electrochemistry of our multifunctional systems to those only derived from each of the constituent components was also made and discussed. These Pt complexes can be vacuum-sublimed and applied as emissive dopants for the fabrication of vapor-deposited electrophosphorescent organic light-emitting devices (OLEDs), which generally exhibit good device performance with efficiencies up to 3.6%, 11.0 cd A-1, and 5.8 lm W-1. While the electroluminescence energy resembles that recorded in fluid solutions for these Pt emitters, these monochromatic OLEDs can emit tunable colors by varying the aryl ring substituents and the level of doping. Saliently, single dopant white-light electroluminescence, triggered by the simultaneous fluorescence/phosphorescence emission of the metal complexes and a variation of applied driving voltages, has also been realized based on some of these multifunctional complexes with peak electrophosphorescence efficiencies of 6.8 cd A-1 and 2.6%.


Reliability of traditional and task specific reference tasks to assess peak muscle activation during two different sprint cycling tests.
Neuromuscular activation is considered an important determinant sprint cycling performance but requires reliable EMG amplitude measurements to facilitate sensitive assessments. The reliability of EMG measurements during sprint cycling may depend on the sprint cycling test undertaken (isovelocity or isoinertial accelerating), the reference tasks used for normalisation (isometric MVCs of a series of single muscle groups [ISO-SINGJT] or isometric cycling MVCs [ISO-CYC]), and the efficacy of the normalisation. This study aimed to compare the magnitude and between-session reliability of peak muscle activation (peak rmsEMG) during: isovelocity and isoinerital sprint cycling tests; ISO-SINGJT and ISO-CYC reference tasks; and absolute and normalised EMG during the sprint cycling tests. EMG amplitude was measured over six major muscle groups on both legs and all measurements were made over two sessions in a randomised counterbalanced design. Peak rmsEMG was assessed during both ISO-SINGJT and ISO-CYC MVCs and then during mechanical peak power output (PPO) during isovelocity (120 RPM) and isoinerital acceleration (0 to >150 RPM) sprint tests. Absolute peak rmsEMG and for the sprint tests normalised EMG values were determined, and coefficient of variation and intra-class correlation coefficients used to assess reliability. Peak rmsEMG at PPO during both sprint cycling tests was similar for the six muscle groups measured. Peak rmsEMG was higher during ISO-SINGJT than ISO-CYC for for 3 of the 6 muscle groups, but all muscle groups exhibited similar reliability for both reference tasks. Neither reference task improved the between-session reliability for either sprint test. This data highlights reservations in the use of isometric reference tasks to ascertain changes in peak muscle activation over time in during sprint cycling assessments.


Malaysian nurses' skin care practices of preterm infants: experience vs. knowledge.
This study sought to explore the impact of Malaysian nurses' perceptions, knowledge and experiences in preterm infant skin care practices using a descriptive approach. Questionnaires were distributed to Neonatal Intensive Care Unit (NICU) nurses in one teaching hospital in Malaysia. A knowledge gap was revealed among nurses in both theoretical and practical knowledge of preterm infant skin. Nurses working for more than 5 years in NICU or having a Neonatal Nursing Certificate (NNC) were not predictors of having adequate knowledge of preterm infants' skin care. The results highlight the complex issue of providing effective skin care to preterm infants. However, a specific finding related to nurses' confidence provides some direction for future practice and research initiatives. Clear clinical evidence-based guidelines and Continuing Nursing Education on relevant topics of preterm infants' care may provide the required knowledge for the nurses.


Are women with history of pre-eclampsia starting a new pregnancy in good nutritional status in South Africa and Zimbabwe?
Maternal nutritional status before and during pregnancy is an important contributor to pregnancy outcomes and early child health. The aim of this study was to describe the preconceptional nutritional status and dietary intake during pregnancy in high-risk women from South Africa and Zimbabwe. This is a prospective observational study, nested to the CAP trial. Anthropometric measurements before and during pregnancy and dietary intake using 24-h recall during pregnancy were assessed. The Intake Distribution Estimation software (PC-SIDE) was used to evaluate nutrient intake adequacy taking the Estimated Average Requirement (EAR) as a cut-off point. Three hundred twelve women who had pre-eclampsia in their last pregnancy and delivered in hospitals from South Africa and Zimbabwe were assessed. 73.7 and 60.2% women in South Africa and Zimbabwe, respectively started their pregnancy with BMI above normal (BMI ≥ 25) whereas the prevalence of underweight was virtually non-existent. The majority of women had inadequate intakes of micronutrients. Considering food and beverage intake only, none of the micronutrients measured achieved the estimated average requirement. Around 60% of pregnant women reported taking folic acid or iron supplements in South Africa, but almost none did so in Zimbabwe. We found a high prevalence of overweight and obesity and high micronutrient intake inadequacy in pregnant women who had the previous pregnancy complicated with pre-eclampsia. The obesity figures and micronutrient inadequacy are issues of concern that need to be addressed. Pregnant women have regular contacts with the health system; these opportunities could be used to improve diet and nutrition. PACTR201105000267371 . Registered 06 December 2010.


Community-acquired pneumonia in the central desert and north-western tropics of Australia.
Community-acquired pneumonia (CAP) results in significant morbidity in central and north-western Australia. However, the nature, management and outcome of CAP are poorly documented. The aim of the study was to describe CAP in the Kimberley and Central Desert regions of Australia. Prospective and retrospective cohort studies of inpatient management of adults with CAP at Alice Springs Hospital and six Kimberley hospitals were carried out. We documented demographic data, comorbidities, investigations, causes, CAP severity, outcome and concordance between prescribed and protocol-recommended antibiotics. Two hundred and ninety-three subjects were included. Aboriginal Australians were overrepresented (relative risk 8.1). Patients were notably younger (median age 44.5 years) and disease severity lower than in urban Australian settings. Two patients died within 30 days of admission compared with expected mortality based on Pneumonia Severity Index predictions of seven deaths (chi(2), P= 0.09). Disease severity and outcome did not differ between regions. Management differences were identified, including significantly more investigations, higher rates of critical care and broader antibiotic cover in Central Australia compared with the Kimberley. Sputum culture results showed Gram-negative organisms in both regions. However, Streptococcus pneumoniae was the most frequent organism isolated in the Kimberley and Haemophilus influenzae in Central Australia. CAP in this setting is an Aboriginal health issue. The low mortality observed and results of microbiology investigations support the use of existing antibiotic protocols. Larger studies investigating CAP aetiology are warranted. Addressing social and environmental disadvantage remains the key factors in dealing with the burden of CAP in this setting.


The role of mentoring relationships in the career development of successful deaf persons.
A qualitative study of deaf graduates of Rochester Institute of Technology in New York State who became supervisors in primarily hearing work settings found that having a mentor was a primary and persistent element in their career success. In the deaf individual's early years, generally it was a family member or teacher who conveyed a belief in that individual's abilities, encouraged effort, and helped instill self-esteem and confidence. Parents were often their strongest advocates, and teachers were their advisors and facilitators. In the work setting, a supervisor or coworker often served as a mentor by coaching, advising, and teaching the individual what they needed to know to succeed on the job. In many ways, these "informal" mentors provided the foundation that enabled the deaf individual to break through what are often barriers to career success despite their skills and abilities. The various forms of mentorship and their impact on deaf college graduates are explored.


Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I.
Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia. The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients. Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner. Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.


Long-term histological outcome after post-hypoxic treatment with 100% or 40% oxygen in a model of perinatal hypoxic-ischemic brain injury.
Hypoxic newborns have traditionally been given supplemental oxygen, and until recently, guidelines for neonatal resuscitation recommended that 100% oxygen be used. Exposure to 100% oxygen after hypoxic injury, however, may exacerbate oxidative stress. The current study evaluated the effect of exposure to 100, 40 or 21% oxygen after neonatal hypoxic-ischemic injury on the severity of brain injury after long-term survival. The severity of histological brain injury was not different in animals exposed to 100% oxygen versus room air. Male animals treated with 40% oxygen post-hypoxia had the lowest mean total histology scores, but this was not statistically significant due to the large variation in injury within each treatment group. These results support the growing number of studies in human infants and experimental animals that show no benefit of 100% oxygen over room air for neonatal resuscitation. Our results suggest that post-hypoxia treatment with 40% oxygen may be beneficial, particularly in males. Further studies of the effects of different concentrations of oxygen on brain injury are warranted and should have sufficient power to examine sex differences.


Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study.
Cisplatin is a widely used anti-cancer drug, but its effect is often limited by acquired resistance to the compound during treatment. Here, we use a combination of transmission electron microscopy (TEM) and nanoscale-secondary ion mass spectrometry (NanoSIMS) to reveal differences between cisplatin uptake in human ovarian cancers cells, which are known to be susceptible to acquired resistance to cisplatin. Both cisplatin sensitive and resistant cell lines were studied, revealing markedly less cisplatin in the resistant cell line. In cisplatin sensitive cells, Pt was seen to distribute diffusely in the cells with hotspots in the nucleolus, mitochondria, and autophagosomes. Inductively coupled plasma mass spectrometry (ICP-MS) was used to validate the NanoSIMS results.


Isolation of a novel bioactive protein from an edible mushroom Pleurotus eryngii and its anti-inflammatory potential.
Edible mushrooms are rich sources of bioactive components. In this study, a bioactive protein, PEP, was isolated from an edible mushroom, Pleurotus eryngii, through (NH4)2SO4 precipitation and ion-exchange chromatography. Proteomic analysis by matrix assisted laser desorption ionization-time of flight mass spectrometry showed that PEP was a novel protein with a molecular weight of 40 kDa. PEP exhibited anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages by inhibiting the overproduction of pro-inflammatory mediators including nitric oxide (NO), cytokine IL-1β and IL-6. It was further demonstrated that these anti-inflammatory effects of PEP were associated with the inhibition of inducible nitric oxide synthase (iNOS) expression, and the deactivation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Our results demonstrated that PEP might be a good candidate for anti-inflammation in the gastrointestinal tract, especially in the colon.


How does integrated knowledge translation (IKT) compare to other collaborative research approaches to generating and translating knowledge? Learning from experts in the field.
Research funders in Canada and abroad have made substantial investments in supporting collaborative research approaches to generating and translating knowledge as it is believed to increase knowledge use. Canadian health research funders have advocated for the use of integrated knowledge translation (IKT) in health research, however, there is limited research around how IKT compares to other collaborative research approaches. Our objective was to better understand how IKT compares with engaged scholarship, Mode 2 research, co-production and participatory research by identifying the differences and similarities among them in order to provide conceptual clarity and reduce researcher and knowledge user confusion about these common approaches. We employed a qualitative descriptive method using interview data to better understand experts' perspectives and experiences on collaborative research approaches. Participants' responses were analysed through thematic analysis to elicit core themes. The analysis was centred around the concept of IKT, as it is the most recent approach; IKT was then compared and contrasted with engaged scholarship, Mode 2 research, co-production and participatory research. As this was an iterative process, data triangulation and member-checking were conducted with participants to ensure accuracy of the emergent themes and analysis process. Differences were noted in the orientation (i.e. original purpose), historical roots (i.e. disciplinary origin) and partnership/engagement (i.e. role of partners etc.). Similarities among the approaches included (1) true partnerships rather than simple engagement, (2) focus on essential components and processes rather than labels, (3) collaborative research orientations rather than research methods, (4) core values and principles, and (5) extensive time and financial investment. Core values and principles among the approaches included co-creation, reciprocity, trust, fostering relationships, respect, co-learning, active participation, and shared decision-making in the generation and application of knowledge. All approaches require extensive time and financial investment to develop and maintain true partnerships. This qualitative study is the first to systematically synthesise experts' perspectives and experiences in a comparison of collaborative research approaches. This work contributes to developing a shared understanding of collaborative research approaches to facilitate conceptual clarity in use, reporting, indexing and communication among researchers, trainees, knowledge users and stakeholders to advance IKT and implementation science.


Traditional cardiovascular risk factors measured prior to the onset of inflammatory polyarthritis.
Cardiovascular mortality is increased in patients with seropositive inflammatory polyarthritis (IP). We tested the hypothesis that the increased risk of cardiovascular disease (CVD) can be explained by elevated traditional CVD risk factor levels in persons prior to development of IP. In a population-based, prospective nested case-control study, 25 600 people aged 45-75 yr participated in a health survey, including standard CVD risk factor assessment, between the years 1993 and 1997. There were 91 incident IP cases (one-third were seropositive at presentation) identified during follow-up to the end of July 2001. Baseline CVD risk factors in the IP cases were compared with those in two age/gender-matched controls. Current smokers had an odds ratio of 2.0 (95% CI 1.0-4.0) for IP. Other risk factors, including total and LDL cholesterol, systolic and diastolic blood pressure and obesity, did not differ significantly between cases and controls. Importantly, in combination, using a standard coronary disease risk score, these factors only had a modest association with future IP, and no association when analysis was restricted to the smaller number of cases who were seropositive. Of the traditional cardiovascular risk factors, only smoking increases CVD risk prior to the onset of IP. Therefore the increased CVD observed in these patients is likely to be a consequence of factors operating after the onset of the arthritis.


The association of health and income in the elderly: experience from a southern state of Brazil.
In high income, developed countries, health status tends to improve as income increases, but primarily through the 50(th)-66(th) percentile of income. It is unclear whether the same limitation holds in middle income countries, and for both general assessments of health and specific conditions. Data were obtained from Brazil, a middle income country. In-person interviews with a representative sample of community residents age ≥ 60 (N=6963), in the southern state of Rio Grande do Sul, obtained information on demographic characteristics including household income and number of persons supported, general health status (self-rated health, functional status), depression, and seven physician-diagnosed, self-reported health conditions. Analyses used household income (adjusted for number supported and economies of scale) together with higher order income terms, and controlled for demographics and comorbidities, to ascertain nonlinearity between income and general and specific health measures. In fully controlled analyses income was associated with general measures of health (linearly with self-rated health, nonlinearly with functional status). For specific health measures there was a consistent linear association with depression, pulmonary disorders, renal disorders, and sensory impairment. For musculoskeletal, cardiovascular (negative association), and gastrointestinal disorders this association no longer held when comorbidities were controlled. There was no association with diabetes. Contrary to findings in high income countries, the association of household-size-adjusted income with health was generally linear, sometimes negative, and sometimes absent when comorbidities were controlled.


MicroRNA alterations in Barrett's esophagus, esophageal adenocarcinoma, and esophageal adenocarcinoma cell lines following cranberry extract treatment: Insights for chemoprevention.
Aberrant expression of small noncoding endogenous RNA molecules known as microRNAs (miRNAs) is documented to occur in multiple cancer types including esophageal adencarcinoma (EAC) and its only known precursor, Barrett's esophagus (BE). Recent studies have linked dysregulation of specific miRNAs to histological grade, neoplastic progression and metastatic potential. Herein, we present a summary of previously reported dysregulated miRNAs in BE and EAC tissues as well as EAC cell lines and evaluate a cranberry proanthocyanidin rich extract's (C-PAC) ability to modulate miRNA expression patterns of three human EAC cell lines (JHEso-Ad-1, OE33 and OE19). A review of 13 published studies revealed dysregulation of 87 miRNAs in BE and EAC tissues, whereas 52 miRNAs have been reported to be altered in BE or EAC cell lines, with 48% overlap with miRNA changes reported in tissues. We report for the first time C-PAC-induced modulation of five miRNAs in three EAC cell lines resulting in 26 validated gene targets and identification of key signaling pathways including p53, angiogenesis, T-cell activation and apoptosis. Additionally, mutiple cancer related networks were ideintified as modulated by C-PAC utilizing Kyoto Encyclopedia of Genes and Genomes (KEGG), Protein Analysis Through Evolutionary Relationships (PANTHER), and MetaCore analysis tools. Study results support the cancer inhibitory potential of C-PAC is in part attributable to C-PAC's ability to modify miRNA profiles within EAC cells. A number of C-PAC-modulated miRNAs have been been identified as dysregulated in BE and EAC. Further insights into miRNA dysregulation and modulation by select cancer preventive agents will support improved targeted interventions in high-risk cohorts.


Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema.
Danazol is a synthetic androgen derivative frequently used as prophylaxis in patients with hereditary angioedema (HAE) due to complement-1 esterase inhibitor deficiency. However, danazol has been reported to decrease high-density lipoprotein cholesterol (HDL-C) levels and to adversely affect coagulation parameters, which are considered to be proatherothrombotic. The short- and long-term effects of danazol were evaluated on proatherogenic intermediate end points in healthy volunteers and patients with HAE. Short-term effects were evaluated in healthy men randomly assigned to 200 mg/d of danazol or placebo for 4 weeks in a crossover trial with no washout period. Long-term effects of danazol on lipoproteins, coagulation, and carotid intima-media thickness (CIMT) were evaluated in a cross-sectional study in which patients with HAE treated with danazol, a mean dose of 170 mg/d for >or=2 years, were compared with healthy controls matched for age, sex, and body mass index (BMI). Drug tolerability was assessed by questionnaires and adherence was measured by pill count when drug bottles were returned after every study visit. Patients in the short-term study were 15 men with a mean (SD) age of 32.6 (6.9) years and BMI of 24.3 (4.1) kg/m(2). In the long-term study, patients with HAE were 10 women and 7 men with a mean (SD) age of 41.1 (12.9) years and BMI of 25.4 (2.6) kg/m(2); the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4 (2.6) kg/m(2). Short-term danazol treatment was associated with a decrease from baseline in apolipoprotein A-I of 21% and in HDL-C of 23%. Flow-mediated dilation and coagulation parameters were unaffected after 4 weeks. Longterm danazol treatment did not adversely affect HDL-C concentration (1.1 [0.5] vs baseline, 1.2 [0.5] pmol/L), HDL-related transfer proteins such as paraoxonase-1 activity (92 [62] vs 80 [40] U/mM), cholesteryl-ester transfer protein mass (1.5 [0.4] vs 2.2 [0.6] microg/mL), lecithin cholesterol acyltransferase activity (21.2 [4.5] vs 32.1 [7.2] nmol CE . mL(-1) . h(-1)), plasma phospholipid transfer protein activity (15.4 [1.5] vs 14.9 [1.2] AU), and apolipoproteins between patients with HAE and controls. The mean (SD) CIMT was similar between patients with HAE and controls (0.62 [0.09] vs 0.59 [0.08] mm; P = NS). However, HAE patients using danazol had increased coagulation activation when compared with controls (prothrombin fragments, 286 [119] vs 164 [57] pmol/L, P = 0.002; thrombinantithrombin complex, 3.9 [1.4] vs 2.6 [1.1] microg/L, P = 0.01). Short-term danazol treatment in healthy volunteers was associated with a reduction in HDL-C levels without a significant effect on endothelial function or coagulation parameters. In contrast, patients with HAE treated for >2 years with danazol had increased activation of coagulation, but there were no significant differences in HDL-C or CIMT compared with matched healthy controls.


Temporal characteristics of audiovisual information processing.
In complex natural environments, auditory and visual information often have to be processed simultaneously. Previous functional magnetic resonance imaging (fMRI) studies focused on the spatial localization of brain areas involved in audiovisual (AV) information processing, but the temporal characteristics of AV information flow in these regions remained unclear. In this study, we used fMRI and a novel information-theoretic approach to study the flow of AV sensory information. Subjects passively perceived sounds and images of objects presented either alone or simultaneously. Applying the measure of mutual information, we computed for each voxel the latency in which the blood oxygenation level-dependent signal had the highest information content about the preceding stimulus. The results indicate that, after AV stimulation, the earliest informative activity occurs in right Heschl's gyrus, left primary visual cortex, and the posterior portion of the superior temporal gyrus, which is known as a region involved in object-related AV integration. Informative activity in the anterior portion of superior temporal gyrus, middle temporal gyrus, right occipital cortex, and inferior frontal cortex was found at a later latency. Moreover, AV presentation resulted in shorter latencies in multiple cortical areas compared with isolated auditory or visual presentation. The results provide evidence for bottom-up processing from primary sensory areas into higher association areas during AV integration in humans and suggest that AV presentation shortens processing time in early sensory cortices.